US11834499B1ActiveUtility
Claudin18 antibodies and methods of treating cancer
Est. expiryJul 17, 2039(~13 yrs left)· nominal 20-yr term from priority
G01N 33/57525G01N 33/5759G01N 33/57557C07K 2317/41C07K 16/28A61K 2039/505A61K 47/6803C07K 2317/56C07K 16/30A61K 47/68031G01N 33/5758A61K 47/6849A61P 1/18A61P 35/00C07K 16/2809G01N 33/57492G01N 33/68C07K 2317/24C07K 2317/31C07K 2317/77C07K 2317/92C07K 2317/34C07K 2317/73A61K 2039/545C07K 2317/33C07K 16/283A61K 47/6851
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Claims
Abstract
The present disclosure provides antigen-binding proteins which bind to Claudin-18.2 (CLDN18.2); bispecific antigen-binding proteins which bind to CLDN18.2 and a second antigen; and conjugates thereof. In various aspects, the antigen-binding proteins bind to Extracellular Loop 1 (EL1) of the extracellular domain of CLDN18.2. Related polypeptides, nucleic acids, vectors, host cells, and conjugates are further provided herein. Kits and pharmaceutical compositions comprising such entities are moreover provided. Also provided are methods of making an antigen-binding protein and methods of treating a subject having cancer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. An antigen-binding protein that binds to a human Claudin 18.2 (CLDN 18.2) protein (SEQ ID NO: 1) comprising any of:
a. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42); and-CDR1-3 derived from a light chain variable region comprising the amino acid sequence: DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQ KPGQPPKLLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQN DYSYPFTFGQGTKLEIK (SEQ ID NO: 45);
b. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLSWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFG QGTKLEIK (SEQ ID NO: 43);
c. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLSWYQQKPGQPPKL LFYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTF GQGTKLEIK (SEQ ID NO: 44);
d. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
e. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 130);
f. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 142);
g. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
h. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 141);
i. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 142);
j. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
k. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 141);
l. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKISCKASGYSFTVYYMNWVKQSPEKSLEWIGEIN PSTGGTTYNPKFKAKATLTVDKSSSTAYMQLKSLTSEDSAIYFCVRWADYW GQGTTLTVSS (SEQ ID NO: 40), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVITQDELSNPVTSGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLV YWMSTRASGVSDRFSGSGSGTDFTLEISRVKAEDVGVYYCQQVVYYPYTFG SGTKLEIK (SEQ ID NO: 41);
m. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATI SSGVSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLTKG NAMDYWGQGTLVTVSS (SEQ ID NO: 46), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFG QGTKLEIK (SEQ ID NO: 47);
n. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATI SSGVSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLTKG NAMDYWGQGTLVTVSS (SEQ ID NO: 46), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFTF GQGTKLEIK (SEQ ID NO: 48);
o. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLFNSGNQRNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVYIYPLTFG QGTKLEIK (SEQ ID NO: 149);
p. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 150);
q. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 147);
r. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
s. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
t. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 137);
u. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 137);
v. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
w. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
x. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
y. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
z. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWIGY INPYNDGTNYAQKFQGRVTMTSDTSTSTVYMELSSLRSEDTAVYYCTRGDY WGQGTLVTVSS (SEQ ID NO: 52), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
aa. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWIGY INPYNDGTNYAQKFQGRVTMTSDTSTSTVYMELSSLRSEDTAVYYCTRGDY WGQGTLVTVSS (SEQ ID NO: 52), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
ab. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDTSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 55), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
ac. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDTSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 55), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
ad. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDKSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 56), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
ae CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDKSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 56), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
af. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSDVISWVRQAPGQGLEWMGE SYLRNGNTYYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSYY GNSFAYWGQGTLVTVSS (SEQ ID NO: 57), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSTQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYYYPFTF GQGTKLEIK (SEQ ID NO: 50);
ag. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSDVISWVRQAPGQGLEWMGE SYLRNGNTYYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSYY GNSFAYWGQGTLVTVSS (SEQ ID NO: 57), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNAYYYPFT FGQGTKLEIK (SEQ ID NO: 51);
ah. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKLSCKASGYTFTSDVISWVRQAPGQGLEWIGES YLRNGNTYYAQKFQGRATLTADKSTSTAYMELSSLRSEDTAVYYCARSYYG NSFAYWGQGTLVTVSS (SEQ ID NO: 49), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSTQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYYYPFTF GQGTKLEIK (SEQ ID NO: 50); or
ai. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKLSCKASGYTFTSDVISWVRQAPGQGLEWIGES YLRNGNTYYAQKFQGRATLTADKSTSTAYMELSSLRSEDTAVYYCARSYYG NSFAYWGQGTLVTVSS (SEQ ID NO: 49), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNAYYYPFT FGQGTKLEIK (SEQ ID NO: 51);
aj. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLEWVATII IGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLVKGN AMDYWGQGTSVAVSS (SEQ ID NO: 10), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTTGEKVTMSCKSSQSLLNSGNQKNYLSWYQQIPGQPPKL LFYWASTRESGVPDRFTGSGSGTDFTLTISNVQAEDLAVYYCQNDYSYPFTF GAGTKLELR (SEQ ID NO: 11);
ak. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFTSYTMSWVRQTPEKRLEWVATII IGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLVKGN AMDYWGQGTSVTVSS (SEQ ID NO: 12), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DILMTQSPSSLTVTAGEKVTMTCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASSRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTF GAGTKLELK (SEQ ID NO: 13);
al. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLYWVATI SSGVSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLTKG NAMDYWGQGTSVTVSS (SEQ ID NO: 14), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTGFTLTISSVQAEDLAVYYCQNDYSYPFTF GAGTKLELK (SEQ ID NO: 15);
am. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLVESGGDFVQPGGSRKLSCAVSGFTFSSFGMHWVRQAPEKGLEWVAYI SSGTTNIYYADTVKGRFTVSRDNPKNSLFLHMTSLRSEDTAMYYCVRSGYY GNSLDYWGQGTPLTVSS (SEQ ID NO: 16), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTGFTLTISSVQAEDLAFYYCQNVYIYPLTF GLGTKLELR (SEQ ID NO: 17);
an. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLQQSGAELARPGASVKLSCKASDYTFTSYVISWVKQRTGQGLEWIGEIY PRNGNTYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARSYYGN SFAYWGQGTLVTVSA (SEQ ID NO: 18), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQRPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYCCQNNYYYPFTF GGGTKLGIK (SEQ ID NO: 19);
ao. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLQQSGPELVKPGASVKMSCKASGYTFTSYLMHWVRQKPGLGLDWIGY INPYNDGTNYNAKFIDKATLTSDKTSSTAYMELSSLTSEDSAIYYCTRGDYW GQGTSVTVSS (SEQ ID NO: 20), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLAVTAGEQVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYGFPLTF GAGTKLELK (SEQ ID NO: 21);
ap. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QIQLQQSGAELARPRASVKLSCKASGYTFTSDVISWVKQRPGQGLEWIGESY LRNGNTYYNENFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARSYYGN SFAYWGQGTLVTVSA (SEQ ID NO: 22), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAREKVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNAYYYPFTF GGGTKLEIK (SEQ ID NO: 23);
aq. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLKESGPGLVAPSQSLSITCTVSGFSLNSYGVSWVRQPPGKGLEWLGVIW GDGSTNYHSALKSRLNINKDKSKSQVFLKLNSLQTDDTATYYCARPTRGNA MDYWGQGTSVTVSS (SEQ ID NO: 24), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DVVMTQSPSSLTVTAGEKVTMNCKSSQSLLNSGNQRSYLTWYQQKPGQPPK LLIYWASTRESGAPDRFTGSGSGADFTLTISSVQAEDLAIYYCQNNYNYPFTF GSGTKLEIK (SEQ ID NO: 25);
ar. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVRMSCKASGYTFTSYIMHWVKQKPGQGPEWMGY INPYNDGTNYNEKFKDKATLTSDKSSSTAYMDLSSLTSEDSAVYYCTRGDY WGQGTSVTVSS (SEQ ID NO: 26), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLFYWASTKKSGVPDRFTGSGSRTDFTLTISSVQAEDLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 27);
as. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYLIHWVKQKPGQGLEWIGYI NPYNDATYYNEKFKAKATLTSDKSSSTAYMELSSLTSEDTAIYYCTRGDYW SQGTSVTVSS (SEQ ID NO: 28), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRQSGVPDRFTGSGSGTDFTLTISSVQAEDLTVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 29);
at. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGY FNPYNDDTKYNEKFKGKATLTSDKSSSTAYMDLSSLTSEDSAVYXCTRGDY WGQGTSVTVSS (SEQ ID NO: 30), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMTCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTGASGVPDRFTGSGSGTDFTLTISSAQAADLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 31);
au. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLQQSGPELVKPGASVKMSCKASGYTFTSFLIHWVRQKPGLGLEWIGYIN PYDYGINYNVKFMDKVTLTSDKTSSTAYMELSSLTSADSAIYYCTRGDYWG QGTSVIVSS (SEQ ID NO: 32), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLAVTTGEQVTMNCKSSQSLLNSGNQKNYLTWYQQKTGQSPK LLIYWASTRQSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYGFPLTF GAGTKLELK (SEQ ID NO: 33);
av. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGFTFTSYVMHWVKQKSGQGLEWIGYI NPYNDDIKYNAKFEDKATLTSDRSSSTAYMELSSLTSDDSAVYFCTRGDYW GQGTTLTVSS (SEQ ID NO: 34), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTTGEKVTMDCKSSQSLLNSGNQKNYLTWYQQKSGQPPK LLIYWASIRKSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 35);
aw. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EFQLQQSGPELVKPGASVKISCKASVYSFTGYNMNWVKQSNGKSLEWIGVI NPNYGNTNYNQRFKGKATLTVDQSSSTAYMQLNSLTSEDSAVYYCARSEDY YNIRGASWGQGTLVTVSA (SEQ ID NO: 36), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
QIVLTQSPAIMSASPGQKVTITCSASSTINYMHWYQQKLGSSPKLWIYDTSKL APGVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLELK (SEQ ID NO: 37); and
ax. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLQQSGAELARPGASVKLSCKASGYTFTSYGISWVKQRTGQGLEWIGEIS PRSGNTYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCATGVITTV IPTDWYFDVWGTGTTVTVSS (SEQ ID NO: 38), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSR LHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQHYSKLPPTFGSGTKLEIK (SEQ ID NO: 39).
2. The antigen-binding protein of claim 1 , wherein the antigen-binding protein is selected from the group consisting of:
a. an antigen-binding protein which comprises
i. a heavy chain (HC) variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a light chain (LC) variable region comprising LC CDR1 comprising KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
b. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYTMS (SEQ ID NO: 88), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65) and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASSRES (SEQ ID NO: 112), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
c. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TISSGVSYTY (SEQ ID NO: 67), and HC CDR3 comprising amino acid sequence LTKGNAMDY (SEQ ID NO: 68); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
d. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83);
e. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence DYTFTSYVIS (SEQ ID NO: 89), HC CDR2 comprising amino acid sequence EIYPRNGNTY (SEQ ID NO: 90), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYYYPFT (SEQ ID NO: 113);
f. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLMH (SEQ ID NO: 72), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRQS (SEQ ID NO: 84), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85);
g. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSDVIS (SEQ ID NO: 75), HC CDR2 comprising amino acid sequence ESYLRNGNTY (SEQ ID NO: 76), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSTQSLLNSGNQKNYLT (SEQ ID NO: 86), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNAYYYPFT (SEQ ID NO: 87);
h. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFSLNSYGVS (SEQ ID NO: 91), HC CDR2 comprising amino acid sequence VIWGDGSTN (SEQ ID NO: 92), and HC CDR3 comprising amino acid sequence PTRGNAMDY (SEQ ID NO: 93); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQRSYLT (SEQ ID NO: 114), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYNYPFT (SEQ ID NO: 115);
i. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYIMH (SEQ ID NO: 94), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTKKS (SEQ ID NO: 116), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
j. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLIH (SEQ ID NO: 95), HC CDR2 comprising amino acid sequence YINPYNDATY (SEQ ID NO: 96), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
k. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYVMH (SEQ ID NO: 97), HC CDR2 comprising amino acid sequence YFNPYNDDTK (SEQ ID NO: 98), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTGAS (SEQ ID NO: 119), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
l. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSFLIH (SEQ ID NO: 99), HC CDR2 comprising amino acid sequence YINPYDYGIN (SEQ ID NO: 100), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85);
m. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYVMH (SEQ ID NO: 101), HC CDR2 comprising amino acid sequence YINPYNDDIK (SEQ ID NO: 102), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRKS (SEQ ID NO: 129), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
n. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence VYSFTGYNMN (SEQ ID NO: 103), HC CDR2 comprising amino acid sequence VINPNYGNTN (SEQ ID NO: 104), and HC CDR3 comprising amino acid sequence SEDYYNIRGAS (SEQ ID NO: 105); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence SASSTINYMH (SEQ ID NO: 120), LC CDR2 comprising amino acid sequence DTSKLAP (SEQ ID NO: 121), and LC CDR3 comprising amino acid sequence HQWSSYPPT (SEQ ID NO: 122);
o. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYGIS (SEQ ID NO: 106), HC CDR2 comprising amino acid sequence EISPRSGNTY (SEQ ID NO: 107), and HC CDR3 comprising amino acid sequence GVITTVIPTDWYFDV (SEQ ID NO: 108); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RASQDISNYLN (SEQ ID NO: 123), LC CDR2 comprising amino acid sequence YTSRLHS (SEQ ID NO: 124), and LC CDR3 comprising amino acid sequence QHYSKLPPT (SEQ ID NO: 125); and
p. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYSFTVYYMN (SEQ ID NO: 109), HC CDR2 comprising amino acid sequence EINPSTGGTT (SEQ ID NO: 110), and HC CDR3 comprising amino acid sequence WADY (SEQ ID NO: 111); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO: 126), LC CDR2 comprising amino acid sequence WMSTRAS (SEQ ID NO: 127), and LC CDR3 comprising amino acid sequence QQVVYYPYT (SEQ ID NO: 128);
q. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
r. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
s. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
t. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEO ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEO ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80),
u. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107; and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
v. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising a an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
w. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO:
136 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83);
x. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83); and
y. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO:
132 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
3. The antigen-binding protein of claim 1 , wherein in sections a), b), c) and aj), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively.
4. The antigen-binding protein of claim 1 , wherein in d) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively.
5. The antigen-binding protein of claim 1 , wherein in e) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively.
6. The antigen-binding protein of claim 1 , wherein in f) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively.
7. The antigen-binding protein of claim 1 , wherein in g) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively.
8. The antigen-binding protein of claim 1 , wherein in h) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively.
9. The antigen-binding protein of claim 1 , wherein in i) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively.
10. The antigen-binding protein of claim 1 , wherein in j) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively.
11. The antigen-binding protein of claim 1 , wherein in k) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively.
12. The antigen-binding protein of claim 1 , wherein in o), p), q) and am) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
13. The antigen-binding protein of claim 1 , wherein in r), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
14. The antigen-binding protein of claim 1 , wherein in s) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
15. The antigen-binding protein of claim 1 , wherein in t) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108), respectively.
16. The antigen-binding protein of claim 1 , wherein in u) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108), respectively.
17. The antigen-binding protein of claim 1 , wherein in v) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively.
18. The antigen-binding protein of claim 1 , wherein in w) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively.
19. The antigen-binding protein of claim 1 , wherein in x) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively.
20. The antigen-binding protein of claim 1 , wherein in y) the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively.
21. The antigen-binding protein of claim 1 , wherein in z)-ae) and ao, the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 84, and 85, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 72, 73, and 74, respectively.
22. The antigen-binding protein of claim 1 , wherein in af)-ai) and ap), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 86, 79, and 87, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 75, 76, and 77, respectively.
23. The antigen-binding protein of claim 1 , wherein in ak), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 112, and 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 88, 65, and 66, respectively.
24. The antigen-binding protein of claim 1 , wherein in al), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 79, and 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 67, and 68, respectively.
25. The antigen-binding protein of claim 1 , wherein in an), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 79, and 113, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 89, 90, and 77, respectively.
26. The antigen-binding protein of claim 1 , wherein in aq), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 114, 79, and 115, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 91, 92, and 93, respectively.
27. The antigen-binding protein of claim 1 , wherein in ar), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 116, and 117, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 94, 73, and 74, respectively.
28. The antigen-binding protein of claim 1 , wherein in as), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 118, and 117, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 95, 96, and 74, respectively.
29. The antigen-binding protein of claim 1 , wherein in at), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 119, and 117, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 97, 98, and 74, respectively.
30. The antigen-binding protein of claim 1 , wherein in au), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 118, and 85, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 99, 100, and 74, respectively.
31. The antigen-binding protein of claim 1 , wherein in av), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 81, 129, and 117, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 101, 102, and 74, respectively.
32. The antigen-binding protein of claim 1 , wherein in aw), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 120, 121, and 122, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 103, 104, and 105, respectively.
33. The antigen-binding protein of claim 1 , wherein in ax), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 123, 124, and 125, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 106, 107, and 108, respectively.
34. The antigen-binding protein of claim 1 , wherein in 1), the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 126, 127, and 128, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 109, 110, and 111, respectively.
35. The antigen-binding protein of claim 1 , wherein the antigen-binding protein is selected from the group consisting of scFv, F(ab′) 2 , Fab, Fab′ and Fv.
36. The antigen-binding protein of claim 2 , wherein the antigen-binding protein is selected from the group consisting of scFv, F(ab′)2, Fab, Fab′ and Fv.
37. The antigen-binding protein of claim 1 , which is an antibody.
38. The antigen-binding protein of claim 2 , which is an antibody.
39. The antigen-binding protein of claim 37 or 38 , which is a monoclonal antibody or a humanized antibody.
40. The antigen-binding protein of claim 37 or 38 , wherein the antibody is an IgG antibody.
41. A bispecific antigen-binding protein that binds CLDN18.2 and a second antigen, wherein the antigen-binding protein that binds CLDN18.2 comprises any of:
a. an antigen-binding protein which comprises a light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and a heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively;
b. an antigen-binding protein which comprises a light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively;
c. an antigen-binding protein which comprises a light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and a heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively; and
d. an antigen-binding protein which comprises a light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
42. The bispecific antigen-binding protein of claim 41 , wherein the second antigen is a cell surface protein expressed by a T cell or a component of the T-cell receptor (TCR).
43. The bispecific antigen-binding protein of claim 41 , wherein the antigen-binding protein is selected from the group consisting of scFv, F(ab′) 2 , Fab, Fab′ and Fv.
44. A conjugate comprising an antigen-binding protein that binds to a human Claudin 18.2 (CLDN 18.2) protein (SEQ ID NO: 1) and a cytotoxic agent or a chemotherapeutic agent, wherein the antigen-binding protein is an antigen-binding protein comprising any of:
a. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42); and
CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 45);
b. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLSWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFG QGTKLEIK (SEQ ID NO: 43);
c. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLSWYQQKPGQPPKL LFYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTF GQGTKLEIK (SEQ ID NO: 44);
d. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
e. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGN AMDYWGQGTLVTVSS (SEQ ID NO: 42), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 130);
f. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 142);
g. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
h. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGQ AMDYWGQGTLVTVSS (SEQ ID NO: 138), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 141);
i. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 142);
j. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLQSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 140);
k. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATII IGGSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLVKGS AMDYWGQGTLVTVSS (SEQ ID NO: 139), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLSSGNQKNYLSWYQQKPGQPPK LLFYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFT FGQGTKLEIK (SEQ ID NO: 141);
l. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKISCKASGYSFTVYYMNWVKQSPEKSLEWIGEIN PSTGGTTYNPKFKAKATLTVDKSSSTAYMQLKSLTSEDSAIYFCVRWADYW GQGTTLTVSS (SEQ ID NO: 40), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVITQDELSNPVTSGESVSISCRSSKSLLYKDGKTYLNWFLQRPGQSPQLLV YWMSTRASGVSDRFSGSGSGTDFTLEISRVKAEDVGVYYCQQVVYYPYTFG SGTKLEIK (SEQ ID NO: 41);
m. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATI SSGVSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLTKG NAMDYWGQGTLVTVSS (SEQ ID NO: 46), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPFTFG QGTKLEIK (SEQ ID NO: 47);
n. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYTMSWVRQAPGKGLEWVATI SSGVSYTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRLTKG NAMDYWGQGTLVTVSS (SEQ ID NO: 46), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNDYSYPFTF GQGTKLEIK (SEQ ID NO: 48);
o. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLFNSGNQRNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNVYIYPLTFG QGTKLEIK (SEQ ID NO: 149);
p. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 150);
q. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 147);
r. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
s. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GNSLDYWGQGTLVTVSS (SEQ ID NO: 131), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
t. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 137);
u. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 137);
v. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
w. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GQSLDYWGQGTLVTVSS (SEQ ID NO: 133), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
x. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFQSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 135);
y. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSFGMHWVRQAPGKGLEWVAYI SSGTTNIYYADSVKGRFTVSRDNAKNSLYLQMNSLRAEDTAVYYCVRSGYY GSSLDYWGQGTLVTVSS (SEQ ID NO: 134), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLFSSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNVYIYPLTF GQGTKLEIK (SEQ ID NO: 136);
z. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWIGY INPYNDGTNYAQKFQGRVTMTSDTSTSTVYMELSSLRSEDTAVYYCTRGDY WGQGTLVTVSS (SEQ ID NO: 52), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
aa. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYLMHWVRQAPGQGLEWIGY INPYNDGTNYAQKFQGRVTMTSDTSTSTVYMELSSLRSEDTAVYYCTRGDY WGQGTLVTVSS (SEQ ID NO: 52), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
ab. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDTSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 55), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
ac. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDTSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 55), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
ad. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDKSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 56), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASIRQSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCLNDYGFPLTFG QGTKLEIK (SEQ ID NO: 53);
ae CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGASVKMSCKASGYTFTSYLMHWVRQAPGQGLEWIG YINPYNDGTNYAQKFQGRATLTSDKSTSTAYMELSSLRSEDTAVYYCTRGD YWGQGTLVTVSS (SEQ ID NO: 56), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCLNDYGFPLTF GQGTKLEIK (SEQ ID NO: 54);
af. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSDVISWVRQAPGQGLEWMGE SYLRNGNTYYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSYY GNSFAYWGQGTLVTVSS (SEQ ID NO: 57), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSTQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYYYPFTF GQGTKLEIK (SEQ ID NO: 50);
ag. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSDVISWVRQAPGQGLEWMGE SYLRNGNTYYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSYY GNSFAYWGQGTLVTVSS (SEQ ID NO: 57), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNAYYYPFT FGQGTKLEIK (SEQ ID NO: 51);
ah. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKLSCKASGYTFTSDVISWVRQAPGQGLEWIGES YLRNGNTYYAQKFQGRATLTADKSTSTAYMELSSLRSEDTAVYYCARSYYG NSFAYWGQGTLVTVSS (SEQ ID NO: 49), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERATINCKSTQSLLNSGNQKNYLTWYQQKPGQPPKL LIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNAYYYPFTF GQGTKLEIK (SEQ ID NO: 50);
ai. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLVQSGAEVKKPGSSVKLSCKASGYTFTSDVISWVRQAPGQGLEWIGES YLRNGNTYYAQKFQGRATLTADKSTSTAYMELSSLRSEDTAVYYCARSYYG NSFAYWGQGTLVTVSS (SEQ ID NO: 49), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPDSLAVSLGERVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQNAYYYPFT FGQGTKLEIK (SEQ ID NO: 51);
aj. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLEWVATII IGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLVKGN AMDYWGQGTSVAVSS (SEQ ID NO: 10), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTTGEKVTMSCKSSQSLLNSGNQKNYLSWYQQIPGQPPKL LFYWASTRESGVPDRFTGSGSGTDFTLTISNVQAEDLAVYYCQNDYSYPFTF GAGTKLELR (SEQ ID NO: 11);
ak. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFTSYTMSWVRQTPEKRLEWVATII IGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLVKGN AMDYWGQGTSVTVSS (SEQ ID NO: 12), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DILMTQSPSSLTVTAGEKVTMTCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASSRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTF GAGTKLELK (SEQ ID NO: 13);
al. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
DVKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPEKRLYWVATI SSGVSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCTRLTKG NAMDYWGQGTSVTVSS (SEQ ID NO: 14), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTGFTLTISSVQAEDLAVYYCQNDYSYPFTF GAGTKLELK (SEQ ID NO: 15);
am. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLVESGGDFVQPGGSRKLSCAVSGFTFSSFGMHWVRQAPEKGLEWVAYI SSGTTNIYYADTVKGRFTVSRDNPKNSLFLHMTSLRSEDTAMYYCVRSGYY GNSLDYWGQGTPLTVSS (SEQ ID NO: 16), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLFNSGNQRNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTGFTLTISSVQAEDLAFYYCQNVYIYPLTF GLGTKLELR (SEQ ID NO: 17);
an. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLQQSGAELARPGASVKLSCKASDYTFTSYVISWVKQRTGQGLEWIGEIY PRNGNTYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARSYYGN SFAYWGQGTLVTVSA (SEQ ID NO: 18), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQRPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYCCQNNYYYPFTF GGGTKLGIK (SEQ ID NO: 19);
ao. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLQQSGPELVKPGASVKMSCKASGYTFTSYLMHWVRQKPGLGLDWIGY INPYNDGTNYNAKFIDKATLTSDKTSSTAYMELSSLTSEDSAIYYCTRGDYW GQGTSVTVSS (SEQ ID NO: 20), and CDR L-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLAVTAGEQVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASIRQSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYGFPLTF GAGTKLELK (SEQ ID NO: 21);
ap. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QIQLQQSGAELARPRASVKLSCKASGYTFTSDVISWVKQRPGQGLEWIGESY LRNGNTYYNENFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCARSYYGN SFAYWGQGTLVTVSA (SEQ ID NO: 22), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAREKVTMNCKSTQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNAYYYPFTF GGGTKLEIK (SEQ ID NO: 23);
aq. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLKESGPGLVAPSQSLSITCTVSGFSLNSYGVSWVRQPPGKGLEWLGVIW GDGSTNYHSALKSRLNINKDKSKSQVFLKLNSLQTDDTATYYCARPTRGNA MDYWGQGTSVTVSS (SEQ ID NO: 24), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DVVMTQSPSSLTVTAGEKVTMNCKSSQSLLNSGNQRSYLTWYQQKPGQPPK LLIYWASTRESGAPDRFTGSGSGADFTLTISSVQAEDLAIYYCQNNYNYPFTF GSGTKLEIK (SEQ ID NO: 25);
ar. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVRMSCKASGYTFTSYIMHWVKQKPGQGPEWMGY INPYNDGTNYNEKFKDKATLTSDKSSSTAYMDLSSLTSEDSAVYYCTRGDY WGQGTSVTVSS (SEQ ID NO: 26), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLFYWASTKKSGVPDRFTGSGSRTDFTLTISSVQAEDLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 27);
as. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYLIHWVKQKPGQGLEWIGYI NPYNDATYYNEKFKAKATLTSDKSSSTAYMELSSLTSEDTAIYYCTRGDYW SQGTSVTVSS (SEQ ID NO: 28), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRQSGVPDRFTGSGSGTDFTLTISSVQAEDLTVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 29);
at. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGY FNPYNDDTKYNEKFKGKATLTSDKSSSTAYMDLSSLTSEDSAVYXCTRGDY WGQGTSVTVSS (SEQ ID NO: 30), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTAGEKVTMTCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTGASGVPDRFTGSGSGTDFTLTISSAQAADLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 31);
au. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
VVQLQQSGPELVKPGASVKMSCKASGYTFTSFLIHWVRQKPGLGLEWIGYIN PYDYGINYNVKFMDKVTLTSDKTSSTAYMELSSLTSADSAIYYCTRGDYWG QGTSVIVSS (SEQ ID NO: 32), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLAVTTGEQVTMNCKSSQSLLNSGNQKNYLTWYQQKTGQSPK LLIYWASTRQSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYGFPLTF GAGTKLELK (SEQ ID NO: 33);
av. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EVQLQQSGPELVKPGASVKMSCKASGFTFTSYVMHWVKQKSGQGLEWIGYI NPYNDDIKYNAKFEDKATLTSDRSSSTAYMELSSLTSDDSAVYFCTRGDYW GQGTTLTVSS (SEQ ID NO: 34), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIVMTQSPSSLTVTTGEKVTMDCKSSQSLLNSGNQKNYLTWYQQKSGQPPK LLIYWASIRKSGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCLNDYSFPLTF GAGTKLELK (SEQ ID NO: 35);
aw. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
EFQLQQSGPELVKPGASVKISCKASVYSFTGYNMNWVKQSNGKSLEWIGVI NPNYGNTNYNQRFKGKATLTVDQSSSTAYMQLNSLTSEDSAVYYCARSEDY YNIRGASWGQGTLVTVSA (SEQ ID NO: 36), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
QIVLTQSPAIMSASPGQKVTITCSASSTINYMHWYQQKLGSSPKLWIYDTSKL APGVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWSSYPPTFGSGTKLELK (SEQ ID NO: 37); and
ax. CDR1-3 derived from a heavy chain variable region comprising the amino acid sequence:
QVQLQQSGAELARPGASVKLSCKASGYTFTSYGISWVKQRTGQGLEWIGEIS PRSGNTYYNEKFKGKATLTADKSSSTAYMELRSLTSEDSAVYFCATGVITTV IPTDWYFDVWGTGTTVTVSS (SEQ ID NO: 38), and CDR1-3 derived from a light chain variable region comprising the amino acid sequence:
DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSR LHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQHYSKLPPTFGSGTKLEIK (SEQ ID NO: 39).
45. The conjugate of claim 44 , wherein the antigen-binding protein is an antibody, which is a humanized antibody or a chimeric antibody.
46. A conjugate comprising an antigen-binding protein that binds to a human Claudin 18.2 (CLDN 18.2) protein (SEQ ID NO: 1) or antigen-binding fragment or variant thereof and a cytotoxic agent or a chemotherapeutic agent, wherein the antigen-binding protein comprises any of:
a. an antigen-binding protein which comprises
i. a heavy chain (HC) variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a light chain (LC) variable region comprising LC CDR1 comprising KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
b. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYTMS (SEQ ID NO: 88), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65) and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASSRES (SEQ ID NO: 112), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
c. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TISSGVSYTY (SEQ ID NO: 67), and HC CDR3 comprising amino acid sequence LTKGNAMDY (SEQ ID NO: 68); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
d. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83);
e. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence DYTFTSYVIS (SEQ ID NO: 89), HC CDR2 comprising amino acid sequence EIYPRNGNTY (SEQ ID NO: 90), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYYYPFT (SEQ ID NO: 113);
f. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLMH (SEQ ID NO: 72), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRQS (SEQ ID NO: 84), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85)
g. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSDVIS (SEQ ID NO: 75), HC CDR2 comprising amino acid sequence ESYLRNGNTY (SEQ ID NO: 76), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSTQSLLNSGNQKNYLT (SEQ ID NO: 86), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNAYYYPFT (SEQ ID NO: 87);
h. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFSLNSYGVS (SEQ ID NO: 91), HC CDR2 comprising amino acid sequence VIWGDGSTN (SEQ ID NO: 92), and HC CDR3 comprising amino acid sequence PTRGNAMDY (SEQ ID NO: 93); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQRSYLT (SEQ ID NO: 114), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYNYPFT (SEQ ID NO: 115);
i. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYIMH (SEQ ID NO: 94), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTKKS (SEQ ID NO: 116), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
j. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLIH (SEQ ID NO: 95), HC CDR2 comprising amino acid sequence YINPYNDATY (SEQ ID NO: 96), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
k. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYVMH (SEQ ID NO: 97), HC CDR2 comprising amino acid sequence YFNPYNDDTK (SEQ ID NO: 98), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTGAS (SEQ ID NO: 119), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
l. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSFLIH (SEQ ID NO: 99), HC CDR2 comprising amino acid sequence YINPYDYGIN (SEQ ID NO: 100), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85);
m. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYVMH (SEQ ID NO: 101), HC CDR2 comprising amino acid sequence YINPYNDDIK (SEQ ID NO: 102), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRKS (SEQ ID NO: 129), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117);
n. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence VYSFTGYNMN (SEQ ID NO: 103), HC CDR2 comprising amino acid sequence VINPNYGNTN (SEQ ID NO: 104), and HC CDR3 comprising amino acid sequence SEDYYNIRGAS (SEQ ID NO: 105); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence SASSTINYMH (SEQ ID NO: 120), LC CDR2 comprising amino acid sequence DTSKLAP (SEQ ID NO: 121), and LC CDR3 comprising amino acid sequence HQWSSYPPT (SEQ ID NO: 122);
o. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYGIS (SEQ ID NO: 106), HC CDR2 comprising amino acid sequence EISPRSGNTY (SEQ ID NO: 107), and HC CDR3 comprising amino acid sequence GVITTVIPTDWYFDV (SEQ ID NO: 108); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RASQDISNYLN (SEQ ID NO: 123), LC CDR2 comprising amino acid sequence YTSRLHS (SEQ ID NO: 124), and LC CDR3 comprising amino acid sequence QHYSKLPPT (SEQ ID NO: 125); and
p. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYSFTVYYMN (SEQ ID NO: 109), HC CDR2 comprising amino acid sequence EINPSTGGTT (SEQ ID NO: 110), and HC CDR3 comprising amino acid sequence WADY (SEQ ID NO: 111); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO: 126), LC CDR2 comprising amino acid sequence WMSTRAS (SEQ ID NO: 127), and LC CDR3 comprising amino acid sequence QQVVYYPYT (SEQ ID NO: 128);
q. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
r. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
s. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
t. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80),
u. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107; and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
v. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising a an amino acid sequence KSSQSLLQSGNQKNYLS (SEO ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80);
w. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO: 136 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83);
x. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83); and
y. an antigen-binding protein which comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO: 132 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
47. The conjugate of claim 46 , wherein the antigen-binding protein is an antibody, which is a humanized antibody or a chimeric antibody.
48. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a heavy chain (HG) variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a light chain (LC) variable region comprising LC CDR1 comprising KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
49. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYTMS (SEQ ID NO: 88), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65) and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASSRES (SEQ ID NO: 112), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
50. The conjugate of claim 46 , wherein the antigen-binding protein comprises:
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TISSGVSYTY (SEQ ID NO: 67), and HC CDR3 comprising amino acid sequence LTKGNAMDY (SEQ ID NO: 68); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
51. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
52. The conjugate of 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence DYTFTSYVIS (SEQ ID NO: 89), HC CDR2 comprising amino acid sequence EIYPRNGNTY (SEQ ID NO: 90), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYYYPFT (SEQ ID NO: 113).
53. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLMH (SEQ ID NO: 72), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRQS (SEQ ID NO: 84), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85).
54. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSDVIS (SEQ ID NO: 75), HC CDR2 comprising amino acid sequence ESYLRNGNTY (SEQ ID NO: 76), and HC CDR3 comprising amino acid sequence SYYGNSFAY (SEQ ID NO: 77); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSTQSLLNSGNQKNYLT (SEQ ID NO: 86), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNAYYYPFT (SEQ ID NO: 87).
55. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFSLNSYGVS (SEQ ID NO: 91), HC CDR2 comprising amino acid sequence VIWGDGSTN (SEQ ID NO: 92), and HC CDR3 comprising amino acid sequence PTRGNAMDY (SEQ ID NO: 93); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQRSYLT (SEQ ID NO: 114), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNNYNYPFT (SEQ ID NO: 115).
56. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYIMH (SEQ ID NO: 94), HC CDR2 comprising amino acid sequence YINPYNDGTN (SEQ ID NO: 73), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTKKS (SEQ ID NO: 116), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117).
57. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYLIH (SEQ ID NO: 95), HC CDR2 comprising amino acid sequence YINPYNDATY (SEQ ID NO: 96), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117).
58. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYVMH (SEQ ID NO: 97), HC CDR2 comprising amino acid sequence YFNPYNDDTK (SEQ ID NO: 98), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTGAS (SEQ ID NO: 119), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117).
59. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSFLIH (SEQ ID NO: 99), HC CDR2 comprising amino acid sequence YINPYDYGIN (SEQ ID NO: 100), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASTRQS (SEQ ID NO: 118), and LC CDR3 comprising amino acid sequence LNDYGFPLT (SEQ ID NO: 85).
60. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFTSYVMH (SEQ ID NO: 101), HC CDR2 comprising amino acid sequence YINPYNDDIK (SEQ ID NO: 102), and HC CDR3 comprising amino acid sequence GDY (SEQ ID NO: 74); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLT (SEQ ID NO: 81), LC CDR2 comprising amino acid sequence WASIRKS (SEQ ID NO: 129), and LC CDR3 comprising amino acid sequence LNDYSFPLT (SEQ ID NO: 117).
61. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence VYSFTGYNMN (SEQ ID NO: 103), HC CDR2 comprising amino acid sequence VINPNYGNTN (SEQ ID NO: 104), and HC CDR3 comprising amino acid sequence SEDYYNIRGAS (SEQ ID NO: 105); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence SASSTINYMH (SEQ ID NO: 120), LC CDR2 comprising amino acid sequence DTSKLAP (SEQ ID NO: 121), and LC CDR3 comprising amino acid sequence HQWSSYPPT (SEQ ID NO: 122).
62. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYTFTSYGIS (SEQ ID NO: 106), HC CDR2 comprising amino acid sequence EISPRSGNTY (SEQ ID NO: 107), and HC CDR3 comprising amino acid sequence GVITTVIPTDWYFDV (SEQ ID NO: 108); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RASQDISNYLN (SEQ ID NO: 123), LC CDR2 comprising amino acid sequence YTSRLHS (SEQ ID NO: 124), and LC CDR3 comprising amino acid sequence QHYSKLPPT (SEQ ID NO: 125).
63. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GYSFTVYYMN (SEQ ID NO: 109), HC CDR2 comprising amino acid sequence EINPSTGGTT (SEQ ID NO: 110), and HC CDR3 comprising amino acid sequence WADY (SEQ ID NO: 111); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO: 126), LC CDR2 comprising amino acid sequence WMSTRAS (SEQ ID NO: 127), and LC CDR3 comprising amino acid sequence QQVVYYPYT (SEQ ID NO: 128).
64. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
65. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising amino acid sequence LVKGNAMDY (SEQ ID NO: 66); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
66. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
67. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGQAMDY (SEQ ID NO: 138 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEQ ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
68. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107; and
ii. a LC variable region comprising LC CDR1 comprising amino acid sequence KSSQSLLNSGNQKNYLS (SEQ ID NO: 78), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
69. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSYTMS (SEQ ID NO: 64), HC CDR2 comprising amino acid sequence TIIIGGSYTY (SEQ ID NO: 65), and HC CDR3 comprising an amino acid sequence LVKGSAMDY (SEQ ID NO: 139 starting at position 99 and ending at position 107); and
ii. a LC variable region comprising LC CDR1 comprising a an amino acid sequence KSSQSLLQSGNQKNYLS (SEQ ID NO: 140 starting at position 24 and ending at position 40) or KSSQSLLSSGNQKNYLS (SEO ID NO: 130 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNDYSYPFT (SEQ ID NO: 80).
70. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising amino acid sequence SGYYGNSLDY (SEQ ID NO: 71); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO: 136 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
71. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising amino acid sequence KSSQSLFNSGNQRNYLT (SEQ ID NO: 82), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
72. The conjugate of claim 46 , wherein the antigen-binding protein comprises
i. a HC variable region comprising HC CDR1 comprising amino acid sequence GFTFSSFGMH (SEQ ID NO: 69), HC CDR2 comprising amino acid sequence YISSGTTNIY (SEQ ID NO: 70), and HC CDR3 comprising an amino acid sequence SGYYGQSLDY (SEQ ID NO: 133 starting at position 99 and ending at position 108) or SGYYGSSLDY (SEQ ID NO: 134 starting at position 99 and ending at position 108); and
ii. a LC variable region comprising a LC CDR1 comprising an amino acid sequence KSSQSLFQSGNQRNYLT (SEQ ID NO: 135 starting at position 24 and ending at position 40) or KSSQSLFSSGNQRNYLT (SEQ ID NO: 132 starting at position 24 and ending at position 40), LC CDR2 comprising amino acid sequence WASTRES (SEQ ID NO: 79), and LC CDR3 comprising amino acid sequence QNVYIYPLT (SEQ ID NO: 83).
73. A conjugate comprising an antigen-binding protein that binds to a human Claudin 18.2 (CLDN 18.2) protein (SEQ ID NO: 1) or antigen-binding fragment or variant thereof and a cytotoxic agent or a chemotherapeutic agent, wherein the antigen-binding protein comprises any of
a. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively;
b. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively;
c. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 64, 65, and 66, respectively;
d. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively;
e. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively;
f. an antigen-binding protein comprising alight chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively;
g. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 78, 79, and 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively;
h. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively;
i. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively;
j. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively;
k. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively;
l. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively;
m. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108), respectively;
n. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108), respectively;
o. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively;
p. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively;
q. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively;
r. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively;
s. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 84, and 85, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 72, 73, and 74, respectively;
t. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 86, 79, and 87, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 75, 76, and 77, respectively;
u. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 112, and 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 88, 65, and 66, respectively;
v. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 79, and 80, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 64, 67, and 68, respectively;
w. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 79, and 113, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 89, 90, and 77, respectively;
x. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 114, 79, and 115, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 91, 92, and 93, respectively;
y. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 116, and 117, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 94, 73, and 74, respectively;
z. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 118, and 117, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 95, 96, and 74, respectively;
aa. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 119, and 117, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 97, 98, and 74, respectively;
ab. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 118, and 85, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 99, 100, and 74, respectively;
ac. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 81, 129, and 117, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 101, 102, and 74, respectively;
ad. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 120, 121, and 122, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 103, 104, and 105, respectively;
ae. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 123, 124, and 125, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 106, 107, and 108, respectively; and
af. an antigen-binding protein comprising a light chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 126, 127, and 128, respectively, and a heavy chain CDR1-3 which comprise the amino acid sequence of SEQ ID NOS: 109, 110, and 111, respectively.
74. The conjugate of claim 73 , wherein the antigen-binding protein is an antibody, which is a humanized antibody or a chimeric antibody.
75. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively.
76. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 138 starting at position 99 and ending at position 107, respectively.
77. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 140 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively.
78. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 130 starting at position 24 and ending at position 40, SEQ ID NO:79, and SEQ ID NO:80, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 64, SEQ ID NO: 65, and SEQ ID NO: 139 starting at position 99 and ending at position 107, respectively.
79. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
80. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 69, 70, and 71, respectively.
81. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108), respectively.
82. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NOS: 82, 79, and 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108), respectively.
83. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively.
84. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 133 starting at position 99 and ending at position 108, respectively.
85. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 135 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively.
86. The conjugate of claim 73 , wherein the antigen-binding protein comprises the light chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 136 starting at position 24 and ending at position 40, SEQ ID NO: 79, and SEQ ID NO: 83, respectively, and the heavy chain CDR1-3 comprise the amino acid sequence of SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 134 starting at position 99 and ending at position 108, respectively.
87. The conjugate of claim 44 , 46 , 48 , 51 , 65 , 70 or 73 , wherein the antigen-binding protein is selected from the group consisting of scFv, F(ab′) 2 , Fab, Fab′ and Fv.
88. The conjugate of claim 74 , wherein the antibody is a monoclonal antibody.
89. The conjugate of claim 88 , wherein the monoclonal antibody is an IgG antibody.
90. The conjugate of claim 40 or 89 , wherein the IgG is selected from IgG1, IgG2, IgG3 and IgG4.
91. The conjugate of claim 44 , 46 , 48 , 51 , 65 , 70 or 73 further comprising a linker located between the antigen-binding protein and the cytotoxic agent or chemotherapeutic agent.
92. The conjugate of claim 44 , 46 , 48 , 51 , 65 , 70 or 73 , wherein the chemotherapeutic agent is an anti-mitotic agent which inhibits cell division by blocking tubulin polymerization.
93. The conjugate of claim 92 , wherein the anti-mitotic agent is an auristatin.
94. The conjugate of claim 93 , wherein the auristatin is MMAE.
95. The conjugate of claim 91 , wherein the linker is a cleavable linker.
96. The conjugate of claim 95 , wherein the cleavable linker is any of VC-PAB, GGFG and CLA2.
97. The conjugate of claim 44 , 46 , 48 , 51 , 65 , 70 or 73 , wherein the conjugate comprises VC-PAB-MMAE.
98. The conjugate of claim 44 , 46 , 48 , 51 , 65 , 70 or 73 , wherein the agent is conjugated at a specific site of the antigen-binding protein.
99. The conjugate of claim 98 , wherein the specific site is an unpaired cysteine residue.Cited by (0)
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